Summary of Work: Transporting epithelia, such as kidney, liver and choroid plexus, remove potentially toxic chemicals from the body and from protected fluid compartments, e.g., cerebrospinal fluid and aqueous humor, and thus play a major role in limiting xenobiotic action. We are using comparative models (renal proximal tubules and hepatocytes from lower vertebrates and invertebrates and mammalian cells in culture derived from kidney, choroid plexus and eye) in combination with fluorescence microscopy (conventional and confocal), video imaging, intracellular microinjection and isolated membrane vesicle techniques to define the cellular mechanisms that drive xenobiotic transport. Recent discoveries include: 1) vesicle mediated and microtubule-dependent transcellular transport of organic anions and organic cations in renal proximal tubule, liver and choroid plexus, 2) a Na-independent, excretory transport system for large organic anions in renal proximal tubule, and 3) potent uptake and efflux mechanisms for organic anions, e.g., prostaglandins, in trabecular meshwork endothelial cells from human eye. Second, we will evaluate the role of competition for excretory transport as a mechanism underlying toxic interactions between xenobiotics. In this regard, preliminary data for renal proximal tubule demonstrate 1) interactions between grapefruit juice flavonoids and drugs handled by renal p-glycoprotein, e.g., cyclosporins and Ca channel blockers, and 2) interactions between phenolphthalein-glucoronide and transporters for organic anions and p-glycoprotein substrates.